Analysis of Epstein Barr virus type III latency on cellular miRNA gene expression

描述(申请人提供)：爱泼斯坦-巴尔病毒是一种致癌性疱疹病毒，与人类的许多恶性肿瘤密切相关。EBV相关肿瘤发生的遗传学基础是EBV潜伏期相关基因和不同细胞遗传学改变的协同作用。在有免疫能力的个体中，由于几种EBV编码的潜伏期基因产物具有高度的免疫遗传性，所以可以耐受最低限度的EBV潜伏期基因表达。然而，在艾滋病患者中，潜伏基因的完全重复表达有时是可以容忍的，因此需要较少的细胞遗传变化就能引起恶性细胞群。这可能在一定程度上解释了艾滋病患者对EBV相关性非霍奇金淋巴瘤的易感性大大增加。与KSHV相关的恶性肿瘤不同，在艾滋病患者中使用HAART疗法对艾滋病/EBV相关的非霍奇金淋巴瘤的数量影响很小。 过去几年的一系列出版物提供了令人信服的证据，证明被称为microRNAs(MiRNAs)的小的非编码RNA基因不仅在正常的细胞信号中发挥重要作用，而且在广泛的癌症中也发挥着关键作用。根据以往研究表明EBV潜伏期相关基因产物通过激活基因表达来传递信号，以及越来越多的证据表明miRNAs在细胞信号转导中的作用，我们假设潜伏期相关病毒基因产物影响细胞miRNA基因的表达。我们进一步假设，细胞miRNA表达谱的变化调节影响病毒生命周期的关键信号转导途径，并可能在EB病毒相关的艾滋病患者的肿瘤发生中发挥作用。公共卫生相关性：EB病毒与许多人类癌症有关，包括鼻咽癌、霍奇金氏病、伯基特淋巴瘤以及艾滋病患者的一些B细胞淋巴瘤。我们的研究主要旨在探讨III型病毒潜伏基因产物对细胞miRNA基因表达的作用，以及这可能如何影响宿主细胞环境，以促进病毒的生命周期，并影响EBV介导的艾滋病和移植患者的肿瘤发生。

DESCRIPTION (provided by applicant): The Epstein Barr virus is an oncogenic herpesvirus that is intimately involved in a number of malignancies in humans. The genetic basis of EBV associated oncogenesis is the concerted action of EBV latency associated genes and varying cellular genetic alterations. In immuno-competent individuals minimal EBV latency gene expression can be tolerated due to the high immunogeneticity of several of the EBV encoded latency gene products. In AIDS patients, however, expression of the full repriotrore of latency genes can sometimes be tolerated and therefore fewer cellular genetic alterations are required to give rise to malignant cell populations. This likely explains in part, the greatly increased susceptibility of AIDS patients to EBV associated non-Hodgkin's lymphomas. Unlike KSHV associated malignancies, the use of HAART therapy in AIDS patients has had a minimal influence on the number of AIDS/EBV associated non-Hodgkin's lymphomas. An array of publications in the last few years have provided compelling evidence that the small non-coding RNA genes referred to as microRNAs (miRNAs) not only play important roles in normal cellular signaling but that they are also key players in a wide array of cancers. Based on previous studies showing that EBV latency associated gene products signal through the activation of gene expression and based on the accumulating evidence indicating the role of miRNAs in cellular signaling, we hypothesize that latency associated viral gene products influence cellular miRNA gene expression. We further hypothesize that alterations in cellular miRNA expression profiles regulate key signal transduction pathways that influence the life cycle of the virus and may play a role in EBV associated oncogenesis in AIDS patients. PUBLIC HEALTH RELEVANCE: EBV is associated with a number of human cancers including nasopharyngeal carcinoma, Hodgkin's disease, Burkitt's lymphoma as well as a number of B-cell lymphomas in AIDS patients. Our studies are principally aimed at addressing the role of type III viral latency gene products on cellular miRNA gene expression and how this may influence the host cell environment to facilitate the life cycle of the virus and to influence EBV mediated oncogenesis in AIDS and transplant patients.